Lysosomal storage disorders and Parkinson's disease: Gaucher disease and beyond

Abstract

Parkinson's disease is associated with mutations in the glucocerebrosidase gene, which result in the enzyme deficiency causing Gaucher disease, the most common lysosomal storage disorder. We have performed an exhaustive literature search and found that additional lysosomal storage disorders might be associated with Parkinson's disease, based on case reports, the appearance of pathological features such as α-synuclein deposits in the brain, and substantia nigra pathology. Our findings suggest that the search for biochemical and cellular pathways that link Parkinson's disease with lysosomal storage disorders should not be limited exclusively to changes that occur in Gaucher disease, such as changes in glucocerebrosidase activity or in glucosylceramide levels, but rather include changes that might be common to a wide variety of lysosomal storage disorders. Moreover, we propose that additional genetic, epidemiological, and clinical studies should be performed to check the precise incidence of mutations in genes encoding lysosomal proteins in patients displaying Parkinson's symptoms.

α-Synuclein–induced lysosomal dysfunction occurs through disruptions in protein trafficking in human midbrain synucleinopathy models

“…Loss-of-function mutations in metabolic genes have recently been recognized as important risk factors for common neurodegenerative disorders such as Parkinson's and Alzheimer's disease (23,24). A well-established example of this is the relationship between GD and PD, where mutations in GBA1 lead to increased risk for PD (6).…”

Novel Activity‐Based Probes for Broad‐Spectrum Profiling of Retaining β‐Exoglucosidases In Situ and In Vivo

“…[1][2][3][4][5][6] Deficiency of GBA1 forms the basis for the most common inherited lysosomal storage disorder, Gaucher disease. [2] Recently, mutations of GBA1 have been reported to markedly increase the risk for Parkinsonism, [7][8][9] and excessive degradation of glucosylceramide by GBA2 may play a role in neuropathology. [4,[10][11][12] The cytosolic broadspecificity b-glucosidase (GBA3) is thought to be involved in degrading xenobiotic b-glucosides.…”

Development of targeted therapies for Parkinson's disease and related synucleinopathies

“…In these diseases, a defi ciency of hexosaminidase A and/or B leads to a buildup of GM2 that leads to neurodegeneration. Both diseases are associated with development of Lewy bodies and synuclein aggregates ( 7,8 ). As in the case of GlcCer, GM2 also has been shown to interact with synuclein and may contribute to neurodegeneration via a similar feedback loop, as proposed for glucocerebrosidase and synuclein ( 49,50 ).…”

“…In NPC disease, a defect in the cholesterol transporters, NPC1 or NPC2, leads to lysosomal accumulation of cholesterol, GlcCer, and downstream glycosphingolipids ( 38,39 ), along with accumulation of synuclein in brain tissue ( 7,8 ). Recent studies have suggested that, as with GBA mutations, patients heterozygous for mutations in NPC1 may develop PD ( 40 ).…”

“…More than 50 LSDs are known and are usually classifi ed according to the nature of the accumulating substrate. Pathology in the CNS is a common feature of most LSDs ( 7,8 ). While the best example of this is the link between Gaucher's disease (GD) and parkinsonism, the link between other LSDs and PD is suggested, but less well documented due to the small number of patients ( 8 ).…”